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Antibiotics that target protein synthesis

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Abstract The key role of the bacterial ribosome makes it an important target for antibacterial agents. Indeed, a large number of clinically useful antibiotics target this complex translational ribonucleoprotein machinery. The majority of these compounds, mostly of natural origin, bind to one of the three key ribosomal sites: the decoding (or A‐site) on the 30S, the peptidyl transferase center (PTC) on the 50S, and the peptide exit tunnel on the 50S. Antibiotics that bind the A‐site, such as the aminoglycosides, interfere with codon recognition and translocation. Peptide bond formation is inhibited when small molecules like oxazolidinones bind at the PTC. Finally, macrolides tend to block the growth of the amino acid chain at the peptide exit tunnel. In this article, the major classes of antibiotics that target the bacterial ribosome are discussed and classified according to their respective target. Notably, most antibiotics solely interact with the RNA components of the bacterial ribosome. The surge seen in the appearance of resistant bacteria has not been met by a parallel development of effective and broad‐spectrum new antibiotics, as evident by the introduction of only two novel classes of antibiotics, the oxazolidinones and lipopeptides, in the past decades. Nevertheless, this significant health threat has revitalized the search for new antibacterial agents and novel targets. High resolution structural data of many ribosome‐bound antibiotics provide unprecedented insight into their molecular contacts and mode of action and inspire the design and synthesis of new candidate drugs that target this fascinating molecular machine. WIREs RNA 2011 2 209–232 DOI: 10.1002/wrna.60 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions Translation > Ribosome Structure/Function

The main steps of translation.

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Antibiotics that target the ribosome, but not at the A‐, P‐, and E‐sites.

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(a) Overlap of the crystal structure of erythromycin (orange) in the H50S (PDB: 1YI2, 2.65 Å) with telithromycin (gray) in the D50S (PDB: 1P9X, 3.41 Å). (b) Overlap of the crystal structure of telithromycin (magenta) in the H50S (PDB: 1YIJ, 2.60 Å) with telithromycin (gray) in the D50S (PDB: 1P9X, 3.40 Å).

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14‐, 15‐, and 16‐membered ring macrolides and ketolides.

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(a) Crystal structure of linezolid bound to the H50S (PDB: 3CPW, 2.70 Å). (b) Crystal structure of linezolid bound to the H50S (PDB: 3CPW, 2.70 Å) overlapped with the crystal structure of native H50S (PDB: 3CC2, 2.40 Å). (c) Crystal structure of linezolid bound to the H50S (PDB: 3CPW, 2.70 Å) overlapped with the crystal structure of linezolid bound to the D50S (PDB: 3DLL, 3.50 Å).

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Antibiotics that bind to the PTC.

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(a) An overlap of the crystal structures of neomycin (PDB: 2ET4, 2.40 Å), tobramycin (PDB: 1LC4, 2.54 Å), and paromomycin (PDB: 1J7T, 2.50 Å) in an A‐site model construct. (b) Conserved contacts of neamine.

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Aminoglycosides and derivatives and mimics of aminoglycosides.

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(a) Crystal structure of a section of the 30S ribosomal subunit (PDB: 1J5E, 3.05 Å). (b) Crystal structure of a portion of the 30S ribosomal subunit complexed with an mRNA fragment and cognate tRNA anticodon stem‐loop bound at the A‐site (PDB: 1IBM, 3.31 Å). (c) Crystal structure of a portion of the 30S ribosomal subunit complexed with an mRNA fragment and cognate tRNA anticodon stem‐loop bound at the A‐site with paromomycin (PDB: 1IBL, 3.11 Å).

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Crystal structure of three tRNA molecules interacting with an mRNA molecule and the 16s rRNA in the 30S ribosome (PDB: 1GIX, 5.50 Å).

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RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions
Translation > Ribosome Structure/Function

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